A critical role of SHP-1 in regulation of type 2 inflammation in the lung.
Asthma is a chronic inflammatory disorder of the airways. Type 2 T helper (Th) cell-dominated inflammation in the lung is a hallmark of asthma. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 is a negative regulator in the signaling pathways of many growth factor and cytokine receptors. However, a direct role of SHP-1 in the IL-4/IL-13 signaling pathway has not been established. In this study, we sought to define the function of SHP-1 in the lung by characterizing the pulmonary inflammation of viable motheaten (mev) mice, and to investigate the molecular mechanisms involved. Pulmonary histology, physiology, and cytokine expression of mev mice were analyzed to define the nature of the inflammation, and the gene-deletion approach was used to identify critical molecules involved. In mev mice, we observed spontaneous Th2-like inflammatory responses in the lung, including eosinophilia, mucus metaplasia, airway epithelial hypertrophy, pulmonary fibrosis, and increased airway resistance and airway hyperresponsiveness. The pulmonary phenotype was accompanied by up-regulation of Th2 cytokines and chemokines. Selective deletion of IL-13 or signal transducer and activator of transcription 6, key genes in the Th2 signaling pathway, significantly reduced, but did not completely eliminate, the inflammation in the lung. These findings suggest that SHP-1 plays a critical role in regulating the IL-4/IL-13 signaling pathway and in maintaining lung homeostasis.
Oh
Sun Young
SY
Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Zheng
Tao
T
Kim
Yoon-Keun
YK
Cohn
Lauren
L
Homer
Robert J
RJ
McKenzie
Andrew N J
AN
Zhu
Zhou
Z
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D004848:Epithelium / Q000201:enzymology / Q000473:pathology; D006984:Hypertrophy; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D055271:Mucin 5AC / Q000235:genetics; D009093:Mucus / Q000201:enzymology; D011014:Pneumonia / Q000201:enzymology* / Q000473:pathology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000201:enzymology / Q000473:pathology; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018418:Th2 Cells / Q000378:metabolism
D016207:Cytokines; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse